Evaluation of Antitrypanosomal Dihydroquinolines for Hepatotoxicity, Mutagenicity, and Methemoglobin Formation In Vitro.

N1-Benzylated dihydroquinolin-6-ols and their corresponding esters display exceptional activity against African trypanosomes in vitro, and administration of members of this class of compounds to trypanosome-infected mice results in cures in a first-stage African trypanosomiasis model. Since a quinone imine intermediate has been implicated in the antiparasitic mechanism of action of these compounds, evaluation of the hepatotoxic, mutagenic, and methemoglobin-promoting effects of these agents was performed. 1-Benzyl-1,2-dihydro-2,2,4-trimethylquinolin-6-ol hydrochloride and 1-benzyl-1,2-dihydro-2,2,4-trimethylquinolin-6-yl acetate showed outstanding in vitro selectivity for Trypanosoma brucei compared to the HepG2, Hep3B, Huh7, and PLC5 hepatocyte cell lines.

New antileishmanial candidates and lead compounds.

Although miltefosine and paromomycin were registered as clinical agents against visceral leishmaniasis in the last decade, the antileishmanial drug arsenal still requires improvement, particularly in the area of oral antileishmanial drugs for both visceral and cutaneous diseases. Several new compounds and formulations have displayed promising efficacy in animal models of leishmaniasis, including the 8-aminoquinoline NPC1161, a series of bis-quinolines, DB766, rhodacyanine dyes, amiodarone, and an oral formulation of amphotericin B. Herein we provide a review of those molecules whose antileishmanial properties have been described over the past few years and a brief assessment of the studies required to identify new preclinical antileishmanial candidates.